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PubMed1980

Adrenocortical responses to adrenocorticotrophin in the rat.

The time course of plasma adrenocorticotrophin (ACTH), adrenal cyclic AMP, adrenal corticosterone, and plasma corticosterone was measured in male Sprague-Dawley rats whose endogenous release of ACTH had been blocked (1) following rapid injections of 100 and 300 ng ACTH/100 g body weight, i.v., (2) during prolonged infusions at rates of 1, 2, and 4 ng ACTH/min per 100 g body weight, and (3) after termination of 30-min infusions at rates extending from 0.06 to 8 ng ACTH/min per 100 g body weight. Following injections, the time course of the variables is similar to the one simulated from our models of adrenal cortical secretion, including the simulation of an intermediate variable of our models of the adrenal cortex cell which was presumed to correspond to cyclic AMP. However, during prolonged infusions there is an unexpected overshoot of adrenal cyclic AMP content whereas adrenal and plasma corticosterone concentrations rise to a steady-state value without overshoot. The total amount of cyclic AMP gradually increases following the three increasing infusion rates of ACTH whereas similar levels of plasma corticosterone concentrations are reached at steady state; therefore the saturation of the adrenal cortical secretion is due to a step ulterior to cyclic AMP formation in the steroidogenesis. After 30-min infusions, plasma corticosterone concentration reaches its maximal value following a rate of ACTH input which evokes only a 4-fold increase in adrenal cyclic AMP content; however, there is a 250-fold increase of adrenal cyclic AMP with respect to control value following the higher rates of infusion of ACTH.

Adrenal Cortex↗

PubMed1995

Fasting serum insulin levels and coronary heart disease in a Danish cohort: 17-year follow-up.

AIM: Our objective was to examine the association between the fasting serum insulin level and coronary heart disease (CHD) and cardiovascular disease in 40-year-old men and women. METHODS: In 1976, all of the men and women born in 1936 living in four municipalities in the County of Copenhagen were invited for a health examination. The participation rate was 87% (504 men and 548 women). All of the participants were followed through the Danish register of deaths and the register of hospital admissions until 1993. RESULTS: After controlling for relevant risk factors (sex, fasting glucose, total cholesterol, high density lipoprotein cholesterol, systolic blood pressure, smoking, triglycerides, body mass index, physical activity and alcohol consumption) the P value for the association between the insulin level and CHD or cardiovascular disease was found to be 0.002; the above risk factors did not appear to be intermediate variables in a causal chain from insulin level to the development of CHD or cardiovascular disease. The significant association between body mass index and CHD disappeared when the fasting insulin level was controlled for, and insulin seemed to be an intermediate factor between body mass index and CHD. CONCLUSION: The fasting serum insulin level in both men and women is a very good predictor of the development of CHD and cardiovascular disease even after controlling for relevant confounding factors.

Adult↗

PubMed1992

Methodological problems of time-related variables in occupational cohort studies.

In studies of long-term health effects of occupational exposures it is important that the time patterns of the study exposure and of the relevant confounders should be taken into account in the analysis. The time-related confounders that have been most frequently considered include age at risk, calendar period, duration of employment, length of follow-up, and employment status (active or retired). These factors are related to the healthy worker effect which is more pronounced among active workers, and declines with length of follow-up. Thus, these time-related factors are potential confounders in occupational cohort studies (and in nested case-control studies). It is therefore advisable to routinely control for length of follow-up and employment status, in addition to the usual confounding factors of age at risk and calendar period. However, it should be stressed that this approach will minimise, but not eliminate, confounding due to the healthy worker effect. In particular, direct control for employment status is inadvisable if this constitutes an intermediate variable in the pathway between exposure and disease, and more complex analytical procedures are necessary in such situations. It is also important that the principle exposure under study should also be analyzed in a time-related manner, taking account of the likely induction and latency periods, and the relative etiological importance of exposure intensity, exposure duration and cumulative exposure. The simplest approach is to analyse the cumulative exposure in a time-related manner, and this may suffice when the aim is merely to consider whether or not there is an effect of exposure. However, once it has been provisionally assumed that an effect exists, attention then shifts to understanding the nature of the effect. In this context, the temporal pattern of exposure and outcome can be considered by examining the effects of exposures in specific time windows while controlling for time-related confounders, and for the effects of exposures in other time windows. A more sophisticated approach is direct fitting of a theoretical model of carcinogenesis, such as the Armitage-Doll or Moolgavkar models. However, it should be emphasized that occupational cohort studies only rarely have sufficient numbers, and data of sufficient quality, to permit meaningful conclusions to be drawn from more sophisticated analyses of this type.

Age Factors↗

PubMed1990

Primitive neuroectodermal tumors of the central nervous system. Patterns of expression of neuroendocrine markers, and all classes of intermediate filament proteins.

Snap-frozen samples from 22 primitive neuroectodermal tumors (PNETs) primary in the central nervous system were studied with antibodies to synaptophysin, bombesin, somatostatin, substance P, vasoactive intestinal polypeptide, all classes of intermediate filaments, and desmoplakins I and II. Frozen sections were immunostained by the avidin-biotin peroxidase complex and indirect immunofluorescence microscopy methods. Selected cases were also studied by double and triple label immunofluorescence microscopy, and by two-dimensional gel electrophoresis and immunoblot analysis. We found that all 22 PNETs expressed synaptophysin extensively. Focal expression of 2 or more neuropeptides was noted in 10 samples studied. All PNETs expressed vimentin, 21 of 22 expressed glial filament protein (GFP), 16 of 22 expressed neurofilament proteins (NFP), 4 of 22 expressed desmin, and 3 of 22 expressed cytokeratins. In only one case were focal and questionable reactions with desmoplakin antibodies seen. Immunoblots confirmed the presence of desmin. Double and triple immunofluorescence revealed a number of antigenic coexpressions in individual cells including: synaptophysin with vimentin, GFP, NFP and desmin, vimentin-GFP, vimentin-NFP, vimentin-cytokeratin, vimentin-desmin and desmin-NFP; similarly, combinations of vimentin-GFP-NFP, vimentin-GFP-desmin, and vimentin-GFP-cytokeratin were found. The consistent expression of synaptophysin and 2 or more neuropeptides indicates that central nervous system PNETs have significant phenotypic features in common with neuroendocrine tumors. Their complex and variable intermediate filament complement patterns combined with their consistent expression of specific neuroendocrine differentiation markers, suggest that central nervous system PNETs comprise a distinct, albeit heterogeneous group of neoplasms.

Adolescent↗

PubMed1995

Poppers, Kaposi's sarcoma, and HIV infection: empirical example of a strong confounding effect?

Are there empirical examples of strong confounding effects? Textbooks usually show examples of weak confounding or use hypothetical examples of strong confounding to illustrate the paradoxical consequences of not separating out the effect of the studied exposure from that of second factor acting as a confounder. HIV infection is a candidate strong confounder of the spuriously high association reported between consumption of poppers, a sexual stimulant, and risk of Kaposi's sarcoma in the early phase of the AIDS epidemic. To examine this hypothesis, assumptions must be made on the prevalence of HIV infection among cases of Kaposi's sarcoma and on the prevalence of heavy popper consumption according to HIV infection in cases and controls. Results show that HIV infection may have confounded the poppers-Kaposi's sarcoma association. However, it cannot be ruled out that HIV did not qualify as a confounder because it was either an intermediate variable or an effect modifier of the association between popper inhalation and Kaposi's sarcoma. This example provides a basis to discuss the mechanism by which confounding occurs as well as the practical importance of confounding in epidemiologic research.

Confounding Factors, Epidemiologic↗

PubMed1987

Factors influencing treatment outcome and patient satisfaction in a short-term psychiatric ward. A path analysis study of the importance of patient involvement in treatment planning.

Factors influencing treatment outcome and patient satisfaction in a short-term psychiatric treatment programme were analysed using a path analysis method. The programme used two models of treatment planning, one with and one without active participation of the patient in formulating a written treatment contract. A causal structural model, which explained 23% of the variance in the model, was used in the final analysis. The results indicated a positive relationship between a cooperation contract procedure and the level of expectations of improvement as well as high ratings of the importance of the patients own effort in treatment. The level of expectations of improvement were related to the symptom level at discharge and global improvement during treatment, indicating a better treatment outcome for the patients of the cooperation contract group, while the importance of own effort was not related to treatment outcome. Symptoms at discharge were mainly determined by symptoms at admission and global improvement, and also by expectations of improvement, initial psychic status and social background. The explained variance was 63%. Satisfaction with treatment was mainly determined by global improvement, symptoms at discharge and expectations of improvement. The explained variance was 60%. It is concluded that attention to patient expectations of improvement viewed as an important intermediate variable, is related to a an improvement in treatment outcome.

Adult↗

PubMed1986

Encouraging the development of integrated health centres: a critical analysis of lower referral rates.

Dutch government policy places considerable emphasis on the strengthening of the primary health care sector. In this connection, it has been shown that health centres tend to reduce costs. The referral rate for GPs in health centres is considerably lower than for GPs practising alone. The question this raises is whether the lower rates are due to the performance of the GPs or to intermediate variables. Three research projects which cast some light on this issue are examined. The first dealt with a possible explanation by means of structural variables, such as differences in the level of urbanization and the availability of hospital services. The second addressed itself to the question of 'patient mix' and asked whether this is responsible for differences in referral rates, which the third project put the same question in respect to the selection of physicians. All results supported rejection of the hypothesis that the statistical relation between the practice-setting and the referral rate was spurious. A clear result concerning the causality of the relation is not yet available.

Adolescent↗

PubMed1985

Sequence of the viral replicase gene from foot-and-mouth disease virus C1-Santa Pau (C-S8).

The nucleotide sequence of the region including the viral replicase gene, the carboxy terminus of protein P18, and the 3'-extracistronic region of foot-and-mouth disease virus (FMDV) type C1-Santa Pau (C-S8) has been determined from previously cloned cDNA fragments [Villanueva et al., Gene 23 (1983) 185-194]. The comparison with the corresponding gene segments of FMDV of serotypes A or O shows base substitutions in 7.2-8.6% of residues in the replicase gene with no insertions or deletions. This is about fourfold lower variation than found for the region encoding capsid protein VP1 of the corresponding viruses. Intermediate variability (substitution at 16.1-23.6% positions) exists in the 3'-extracistronic region, including point mutations, insertions and deletions. The predicted amino acid sequence of the replicase gene indicates that 75.5-82.6% of mutations are silent and that 93.4% of amino acids are conserved in the four FMDV replicases. The frequency of certain types of silent mutations and of rare codon usage is significantly lower for the replicase gene than for the protein VP1 coding region.

Amino Acid Sequence↗

PubMed1987

A quantitative model of myosin phosphorylation and the photomechanical response of the isolated sphincter pupillae of the frog iris.

The time courses of isometrically recorded photomechanical responses of isolated sphincter pupillae of Rana pipiens can be accurately predicted by a set of differential equations derived from phosphorylation theory of smooth muscle contraction. We compared actual light-stimulated contractions with calculated ones over a wide range of stimulus intensities (56-fold) and durations (0.4-4.0 s). The hypothetical Ca++-calmodulin-myosin light chain kinase cascade acts as a "valve" to control the flow of ATP through a phosphorylation-dephosphorylation cycle. When the rate of flow of ATP through the phosphorylation-dephosphorylation cycle is increased, the percentage of phosphorylated myosin increases. The time courses of the concentrations of phosphorylated myosin during different responses are seen to be functions of the time courses of the opening and closing of the coupling cascade "valve." The calculations predict experimentally measurable intermediate variables, which can aid the investigation of the application of quantitative phosphorylation theory to amphibian sphincter pupillae and to smooth muscle in general.

Adenosine Triphosphate↗

PubMed1987

Bone dynamics: stress, strain and fracture.

Bone is a dynamic tissue whose functional mass is controlled by the balance between the endocrine drive towards bone resorption and the mechanically-engendered drive towards bone formation. Strain is the key intermediate variable between loading forces and bone remodelling. Animal studies have shown that static loading of bone has no osteogenic effect; bone loss occurs as if there were no loading at all. However, dynamic loading, that is, cyclic change in internal strain, is strongly osteogenic, with relatively few cycles required for maximum effect. However, if a sufficient number of cycles is applied, repetitive loading can cause stress fractures. This number decreases as internal strains increase. Thus strain redistribution within bone, as caused by muscle fatigue or improper sports equipment, is a significant cause of fracture.

Aging↗

PubMed1973

Cell contacts in the mouse mammary gland. I. Normal gland in postnatal development and the secretory cycle.

The nature and distribution of cell contacts have been examined in thin sections and freeze-fracture replicas of mammary gland samples from female C3H/Crgl mice at stages from birth through pregnancy, lactation, and postweaning involution. Epithelial cells of major mammary ducts at all stages examined are linked at their luminal borders by junctional complexes consisting of tight junctions, variable intermediate junctions, occasional small gap junctions, and one or more series of desmosomes. Scattered desmosomes and gap junctions link ductal epithelial and myoepithelial cells in all combinations; hemidesmosomes attach myoepithelial cells to the basal lamina. Freeze-fracture replicas confirm the erratic distribution of gap junctions and reveal a loose, irregular network of ridges comprising the continuous tight-junctional belts. Alveoli develop early in gestation and initially resemble ducts. Later, as alveoli and small ducts become actively secretory, they lose all desmosomes and most intermediate junctions, whereas tight and gap junctions persist, The tight-junctional network becomes compact and orderly, its undulating ridges oriented predominantly parallel to the luminal surface. It is suggested that these changes in junctional morphology, occurring in secretory cells around parturition, may be related to the greatly enhanced rate of movement of milk precursors and products through the lactating epithelium, or to the profound and recurrent changes in shape of secretory cells that occur in relation to myoepithelial cell contraction, or to both.

Animals↗

PubMed1992

G-estimation of the effect of prophylaxis therapy for Pneumocystis carinii pneumonia on the survival of AIDS patients.

AIDS Clinical Trial Group Randomized Trial 002 compared the effect of high-dose with low-dose 3-azido-3-deoxythymidine (AZT) on the survival of AIDS patients. Embedded within the trial was an essentially uncontrolled observational study of the effect of prophylaxis therapy for pneumocystis carinii pneumonia on survival. In this paper, we estimate the causal effect of prophylaxis therapy on survival by using the method of G-estimation to estimate the parameters of a structural nested failure time model (SNFTM). Our SNFTM relates a subject's observed time of death and observed prophylaxis history to the time the subject would have died if, possibly contrary to fact, prophylaxis therapy had been withheld. We find that, under our assumptions, the data are consistent with prophylaxis therapy increasing survival by 16% or decreasing survival by 18% at the alpha = 0.05 level. The analytic approach proposed in this paper will be necessary to control bias in any epidemiologic study in which there exists a time-dependent risk factor for death, such as pneumocystis carinii pneumonia history, that (A1) influences subsequent exposure to the agent under study, for example, prophylaxis therapy, and (A2) is itself influenced by past exposure to the study agent. Conditions A1 and A2 will be true whenever there exists a time-dependent risk factor that is simultaneously a confounder and an intermediate variable.

Acquired Immunodeficiency Syndrome↗

PubMed1990

Inhibin and estradiol responses to ovarian hyperstimulation: effects of age and predictive value for in vitro fertilization outcome.

We have compared the time courses of serum inhibin and estradiol responses to ovarian hyperstimulation in patients undergoing in vitro fertilization and embryo transfer as well as their predictive value for outcome of intermediate variables and pregnancy in in vitro fertilization and embryo transfer. Blood samples (n = 749) were collected for up to 6 days before hCG administration in 100 consecutive treatment cycles, of which 44 resulted in pregnancy, as defined by elevated luteal phase serum hCG beta levels. Inhibin and estradiol levels increased markedly in parallel during hyperstimulation and were highly correlated (r = 0.89; P less than 0.001). Inhibin responses were significantly lower in women 35 yr of age or older (P less than 0.001), although estradiol responses were not influenced by age. Gravidity and tubal disease also had marginal effects on the time course of inhibin responses, but not on overall mean inhibin levels or estradiol responses. The time course of hormonal responses to hyperstimulation was not influenced by any other demographic or etiological factors. Peak values of both hormones correlated with the total number of follicles (inhibin, r = 0.70; estradiol, r = 0.65; P less than 0.001) and oocytes retrieved per cycle (inhibin, r = 0.49; estradiol, r = 0.39; P less than 0.001). The time course and peak values of inhibin and estradiol responses to hyperstimulation did not differ significantly between conception or nonconception cycles whether judged by biochemical (luteal hCG beta) or clinical (viable ongoing pregnancy) criteria. Luteal phase serum inhibin, estradiol, progesterone, and hCG levels were significantly higher in conception than in nonconception cycles (P less than 0.001). These data suggest that the rises in serum inhibin and estradiol levels during hyperstimulation have similar predictive properties for IVF-ET outcomes and could, therefore, be used interchangeably to monitor hyperstimulation regimens. The age-related reduction in inhibin, but not estradiol, responses suggests that these two hormones reflect different granulosa cell functions and that serum inhibin responses to maximal ovarian stimulation may be a sensitive and early index of declining ovarian function with advancing age.

Adult↗

PubMedDate not supplied

Regulation and function of the fetal adrenal gland in sheep.

It is now known that in some species (sheep, cow, pig, llama) the fetal adrenal cortex is capable of secreting cortisol both early and late in gestation, but not during some, variable, intermediate time period. In the sheep the fetal adrenal can secrete cortisol, and respond quickly to ACTH, both between 40-90 days of gestation, and from 120-150 days (term), but not between 90-120 days. The inability to secrete cortisol in this 'off' period is due to lack of adequate pituitary ACTH at this time to maintain expression of P-450(17 alpha and P-450scc. Recent experiments demonstrate that the fetal pituitary does secrete adequate amounts of ACTH to keep these genes expressed, in the 40-90 day period. The question now becomes, therefore, what regulates the triphasic secretion pattern of ACTH during fetal sheep development.

Adrenal Glands↗

PubMed1987

Genetic variation and differentiation of three Schistosoma species from the Philippines, Laos, and Peninsular Malaysia.

Electrophoretically-detected allozyme variation is described in strains of Schistosoma japonicum (4 Philippine strains), S. mekongi (Laos), and an undescribed anthropophilic S. japonicum-like schistosome from Peninsular Malaysia. Result, together with those reported previously for 8 other strains (S. japonicum, China, Formosa, Japan, Philippines; S. mekongi, 2 substrains; Malaysian schistosome, 2 strains) permit a composite genetic characterization of 15 strains of Asian schistosomes at 9-18 presumptive loci. The proportion of polymorphic loci (P) and the mean heterozygosity per locus (H) were zero in all strains. Although this was expected for strains that had been in laboratory culture for up to 50 years, we expected to detect variation in strains based on 10-50 recently field-collected infected snails. We expected S. japonicum to be as variable as S. mansoni (P = 0.13 (0-0.33), H = 0.04, 18 loci, 22 strains) as it is believed to reproduce sexually, has an evolutionary history of several million years, inhabits a wide geographic range, coevolved with a genetically variable intermediate snail host, and has a diversity of mammalian hosts. No differences were detected between the 5 S. japonicum strains from Leyte and Luzon (Philippines), between the 3 S. mekongi strains, or between the 3 Malaysian schistosome strains; these groups and the remaining S. japonicum strains representing Mindoro (Philippines), China, Formosa, and Japan each have distinctive multilocus electromorphic patterns. Nei's genetic distances (D) were calculated to estimate interstrain and interspecific divergence. Interstrain genetic distances in S. japonicum averaged greater than 0.3; much higher than those reported previously for S. mansoni (D = 0.06, D(max) = 0.24). S. japonicum (Mindoro) was moderately differentiated from the Leyte-Luzon strains (D = 0.29, 12 loci). Estimates of the S. japonicum China-Philippine distance (D greater than 0.4, 11 loci) are high for conspecific populations and further studies of the still poorly characterized Chinese parasite may reveal that these are, in fact, separate species. S. japonicum is shown to be only distantly related to S. mekongi and the Malaysian schistosome (D greater than 1); the latter is closely related to, but genetically quite distinct from, S. mekongi (D = 0.61 +/- 0.275, 11 loci) and warrants recognition as a new species. The medical significance of the isogenic nature of the Asian schistosome strains and their evolutionary divergence are discussed.

Animals↗

PubMed1992

Risk factors for severe measles.

A retrospective study on measles was carried out in 522 children admitted to the Department of Pediatrics, Sumber Waras Hospital, Jakarta during the period of January 1982-December 1986. Most of the subjects (91.1%) came from lower socio-economic levels, living in unfavorable environmental conditions in crowded housing. The predominant age group was 2-5 years; complications were observed in 82.6% and mortality in 10.3%. The most common complications and cause of deaths were bronchopneumonia (94.4%), encephalopathy (88.9%) and diarrhea (25.9%) or combinations thereof. The outcome of measles infections is determined by the presence of malnutrition and complications which is influenced by the nutritional intake, exposure, susceptibility and constitution of the patients. The household characteristics (socio-economic, socio-cultural and health facilities available) influence the above mentioned interactions through intermediate variables of nutrition (feeding pattern, food supplements), constitution, age) and treatment. Research and intervention on measles can be designed and planned based on this model of interactions.

Acute Disease↗

PubMed1988

Ego and superego alterations in borderline structures: their effect on the process and outcome of treatment.

The intermediate variable establishing the link between pathological structural alterations and aetiopathogenic factors, whether constitutional or acquired, might correspond to mental substructures derived from defensively altered and pathologically internalized object relations. Some basic postulates, connected to this central thesis, guided a brief, introductory critical review of two controversial areas in the treatment of borderline structures: (a) the relationship between mental models and developmental theories and (b) the relationship between mental models and therapeutic approaches. Since the axis of this paper centred around the limitations determined by structural alterations produced by defences, I then outlined some aspects of the treatment of a patient with severe character pathology, laying particular stress on: (a) the clinical manifestations of ego and superego alterations and their influence on the process and outcome of treatment; (b) the impediments and complications stemming from early superego precursors, with reference, in particular, to the therapeutic frame and psychoanalytic tactics; and, finally (c) the limitations and vicissitudes of the interplay of specific and diatrophic (non-specific) aspects of the analytic work in the task of promoting emotional growth.

Adult↗

PubMed1995

Elevated platelet-derived microparticle levels during unstable angina.

OBJECTIVE: To use fluorescent-activated flow cytometry coupled with activation-dependent and -independent platelet-specific monoclonal antibodies in a pilot study to assess the degree and time course of platelet activation events in patients presenting within 24 h of onset of Canadian Cardiovascular Society class 4 angina. BACKGROUND: Although activated platelets play a key role in the pathogenesis of unstable angina, the development of simple assays to quantify platelet activation events directly is lacking. METHODS: Blood samples were drawn from six unstable angina patients from the coronary care every 4 h over a 24 h period into a fixative and analyzed the following day. All patients were on acetylsalicylic acid and heparin. Comparisons were made with six healthy, medication-free volunteers. Platelets were defined by flow cytometry as positive for fluorochrome-labelled monoclonal antibody to glycoprotein Ib (AP1) and within the single intact platelet window defined by scatter characteristics. The presence of the fluorochrome-labelled activation-specific monoclonal antibody (KC4.1 for anti-P-selectin, PAC-1 for activated glycoprotein IIb/IIIa) was used to determine the percentage of activated platelets. Platelet activation-dependent microparticles were identified by gating on AP1-positive events and defining microparticles (percentage of total platelet events) as being smaller (forward size scatter) than single intact platelets. RESULTS: There was a marked, sixfold increase in microparticle generation (17 +/- 7% versus 2.8 +/- 1.4%) in the unstable angina patients (P = 0.001) compared with healthy volunteers. Further assessment of six coronary care unit patients with nonischemic cardiac disorders demonstrated a highly variable intermediate level of microparticle generation (11 +/- 7%). No differences in activated glycoprotein IIb/IIIa expression were noted for the various groups and P-selectin expression was lower in the unstable angina patients (6 +/- 2% versus 12 +/- 3%, (P = 0.007). CONCLUSIONS: This pilot study suggests that measuring circulating platelet microparticle levels is a simple yet useful parameter for the assessment of platelet activation in unstable angina compared with activation markers on intact whole platelets. Despite antiplatelet and antithrombin therapy, significant platelet activation occurred in these patients over the initial 24 h. Flow cytometry may be a useful tool in assessing the efficacy of newer therapeutic modalities.

Adult↗